**6. Conclusions**

Azoospermia, the most severe form of infertility, may represent a biomarker of overall health, serving as a harbinger for higher morbidity and mortality. As reported above, certain

chromosomal anomalies and gene defects underlying azoospermia can be responsible for a wide spectrum of health issues beside azoospermia, including metabolic/cardiovascular disorders, autoimmune diseases, hypogonadism, syndromic conditions and cancers. After the exclusion of all known acquired causes and after performing routine genetic testing, the etiology remains unknown in a substantial proportion of patients and it could be related to ye<sup>t</sup> unidentified genetic/epigenetic factors [3]). The clinical impact of discovering such "hidden" genetic factors is important to predict not only the fertility status but also the general health of these men. For instance, by performing a-CGH analyses, a "CNV burden" (especially deletions) in idiopathic infertile patients have been reported by three research groups [152–154], suggesting a higher genomic instability potentially relevant also for general health. CNV burden together with the above listed shared monogenic factors could be one of the many possible explanations for the higher morbidity and lower life expectancy observed in infertile men in respect to fertile men [6,7,19,152]. Similarly to monogenic disorders, the inheritance of an unstable genome may also have clinical consequences on the offspring's health.

Thanks to the diffusion of Whole Exome Sequencing (WES) in the frame of fruitful international collaborations, the number of genes involved in NOA is rapidly increasing [3,5,155]. Exome analysis has proven to be very efficient in diagnosing the cause of meiotic arrest [75], with potential implications for TESE prognosis. WES allowed the identification of many novel genes, potentially relevant also for tumorigenesis. It can be hypothesized that inherited genetic/epigenetic factors are responsible for the increased risk of certain neurodevelopmental disorders, as well as impaired cardiometabolic and reproductive health profile in children conceived with ICSI from NOA fathers. In this context, the discovery of genetic cause underlying azoospermia would allow not only to improve the managemen<sup>t</sup> of NOA patients, but also to predict the clinical consequences on the offspring inheriting the certain gene defect(s) (Figure 1).

While the list of genetic defects with potential impact on general health increases, it is important to note that apart from a few exceptions, we are still missing a direct evidence for a clear-cut genetic link between NOA and higher morbidity, especially in terms of cancer predisposition. Multicentre efforts are needed in order to collect long-term follow-up data on large groups of genetically well-characterized NOA patients. Apart from the routine karyotype and Y chromosome deletion analysis, we hope that WES analysis will become soon part of the genetic diagnostic work-up of NOA patients allowing diagnosis, TESE prognosis and prevention for general health.

**Author Contributions:** C.K. conceived the manuscript. C.K. and F.C. designed and wrote the manuscript. Both authors have read and agreed to the published version of the manuscript.

**Funding:** The publication of this review article was supported by Next Fertility Procrea, Lugano, Switzerland.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
